Contrast agents, also known as contrast media, are often used during medical imaging examinations to highlight specific parts of the body and make them easier to see. Among them are x-ray contrast media and iodinated non ionic contrast media such as, for instance, diatrizoate, iothalamate, ioxithalamate, metrizoate, iohexyl, iomeprol (The Merck Index, XIII Ed., 2001, No. 5071), iopamidol (The Merck Index, XIII Ed., 2001, No. 5073), iopentol, iopromide, ioversol, ioxilan, iodixanol, iosarcol, iogulamide, ioglunide, iogluamide, acetrizoate, iodamide, iocetamide, ioxaglate, iotrolan, iotasul, iodipamide, iocarmate, iodoxamate, iotroxate, iotrolan, and the like. Additional examples of similar iodinated contrast agents are also described, for instance, in WO 94/14478 (Bracco).
Such compounds may be prepared by a multiplicity of synthetic routes, some of those are characterised by the conversion of aromatic amino derivatives in the corresponding carboxamides, by reaction with a suitable α-hydroxyacid derivative. One representative example of such reaction may be found within the processes for the preparation of Iopamidol as disclosed, for instance, in WO 02/44132, WO 96/37459, WO 96/37460, U.S. Pat. No. 5,362,905, WO 97/47590, WO 98/24757, WO 98/28259 and WO 99/58494. For a general reference to the preparation process of Iopamidol see, e.g., the synthetic path as per Scheme I below:

According to Scheme I, the amino derivative of formula (3) is suitably reacted with (2S)-2-(acetyloxy)propanoyl chloride (4), to provide compound (5).
The compound of formula (3) can be obtained, in its turn, by reacting the starting material of formula (1) with a suitable chlorinating agent, e.g. thionyl chloride. Remarkably, and according to what reported in WO 96/37459, an intermediate sulfinyl derivative of formula (2) can be obtained during the chlorination step.
The compound of formula (5) thus obtained is further reacted with the aminoalcohol of choice, in the present case the 2-amino-1,3-propanediol, better known as serinol, and deprotected at the hydroxy group, so to achieve to Iopamidol of formula (6).
Both these latter reactions are carried out according to conventional methods known in the art, either for the preparation of carboxamides by reacting acyl chloride derivatives with amino compounds, or for the cleavage of the acetyl protecting group from the hydroxyl function.
As per the above Scheme I, compound (4) is the activated reactive form of (2S)-2-hydroxy-propanoic acid, commonly known as L-lactic acid, wherein the hydroxy group is suitably protected as therein reported. It has to be noted, in this respect, that the preparation of compound (4) is time consuming as it requires additional synthetic steps starting from commercially available (2S)-2-hydroxy-propanoic acid sodium salt (7), as illustrated in Scheme II below:

According to Scheme II, the first step is represented by the conversion of compound (7) to L-lactic acid (8), by operating under acidic conditions. The compound thus obtained is then protected at the hydroxy group so as to lead to the corresponding acetylated intermediate (9) that, once recovered and purified, is further converted to the desired acyl chloride (4), by properly functionalizing the carboxylic group with a suitable chlorinating agent, typically thionyl chloride.
Besides the time spending, the protocol according to Scheme II leads to the formation of the desired compound (4) upon a process that contemplates some distillation steps for either the isolation or the purification of the intermediate compounds. Furthermore, despite the fact that each of the above steps may be carried out according to conventional methods, the use of air and/or moisture sensitive reagents, for instance thionyl chloride, may thus require the adoption of reaction conditions rather troublesome, at least when operating with large amounts of substrates and reactants, as per the industrial scale.
By that, it would be particularly advantageous to find out an alternative way to prepare Iopamidol, in high yields and with a high degree of purity, by means of a process comprising reacting any suitable intermediate precursor with an alternative reactant to compound (4).
In this respect, examples for the preparation of given aromatic carboxamido compounds by reacting sulfinyl derivatives with α-hydroxyacids are reported in the literature. See, for instance, Bioorg. Med. Chem. Lett. 2006; 16; 4784-4787; and Bioorg. Med. Chem. Lett. 2007; 17; 6261-6265, wherein an α-hydroxyacid moiety is reacted with aromatic not sterically hindered sulfinyl substrates. Likewise, the reaction of given α-hydroxyacids with suitable sulfinyl derivatives, therein referred to as N-sulfinylamine or even N-sulfinylaniline derivatives, is also reported in Tetrahedron Lett. 2000; 41; 6017-6020; and Tetrahedron Lett. 1986; 27; 1921-1924.
Interestingly, all of the N-sulfinylanilines reported in the aforementioned prior art documents and presently referred to as Ar—N═S═O compounds rely, essentially, on rather simple molecules deriving from:                aniline itself, wherein Ar corresponds to phenyl;        mono-substituted anilines, wherein Ar corresponds to p-chloro-C6H4—, p-methyl-C6H4—, p-nitro-C6H4—; or        di-substituted anilines, wherein Ar represents 2-fluoro-4-methoxycarbonyl-C6H3— or 2,4-dichloro-C6H3.        
To our knowledge, however, such a synthetic method has never been disclosed for the preparation of given carboxamides, in a single step, by starting from sterically hindered compounds, in particular from N-sulfinylanilines fully substituted, namely penta-substituted on the aromatic ring. To this extent, it is worth noting that within the process for the preparation of Iopamidol, the aromatic ring of the above sulfinyl derivatives of formula (2) is fully substituted in positions 3 and 5 by two carbonyl moieties (e.g. —COCl groups) and, remarkably, in positions 2, 4 and 6 by three iodine atoms, known to be particularly bulky substituents.
We have thus found that sterically hindered fully-substituted N-sulfinylanilines are able to react, in a single step and under mild operative conditions, with suitable α-hydroxyacids or a salt thereof, to give the desired carboxamido derivatives, according to an alternative synthetic pathway.